Appointments

Upon an infection, the innate and then the adaptive immune system are rapidly ramped up to control and then clear the infection. When T cells are activated, in addition to developing effector functions that aid in clearing of the infection, they also upregulate members of the tumor necrosis factor receptor (TNFR) family (1). This family of receptors plays an important role in controlling life and death in the immune system. Our lab has shown that the TNFR family members 4-1BB and GITR are critical for sustaining CD8 T cell survival in the lung during acute severe respiratory influenza infection (2, 3). We provided evidence that the immune system uses antigen–inducible TNFRs such as 4-1BB to control the duration of T cell response according to the persistence of the virus, thereby allowing a response that is sufficient to clear the virus, but is down regulated once the virus is cleared to protect the host from pathology (2, 4, 5). This led us to ask what happens when the virus cannot be cleared, such as occurs with HIV infection of humans or lymphocytic choriomeningitis virus clone 13 infection of mice.

In the event that a virus cannot be eliminated from the host, immune regulatory mechanisms come into play that allow a détente to be reached between the host and pathogen, thereby balancing immune control of the pathogen against collateral damage. We showed that although 4-1BB expression persists on the LCMV specific CD8 T cells at the chronic phase of infection with the clone 13 variant of LCMV, the 4-1BB signaling pathway becomes desensitized due to loss of one of its key signaling adaptors, TRAF1 (6). TRAF1 is also lost from HIV specific T cells with progression of HIV, but maintained at higher levels in those individuals that can control their HIV infection(6). Moreover, the TRAF1 levels inversely correlate with viral load. In contrast, we showed that the TNFR family member GITR is differentially regulated during viral infection (3, 7, 8). GITR is turned off during chronic viral infection through persistent downregulation of its ligand, GITRL. Future work in our laboratory will investigate the underlying mechanisms behind the differential role of TNFRs in different infections.

My laboratory also has a strong interest in T cell immunity in humans, with an emphasis on influenza and HIV. In recent studies, we have explored the state of T cell memory to influenza virus in older people and found that the memory CD8 T cells expressed markers of terminal differentiation and senescence commonly found in T cells specific for persisting pathogens such as CMV. We found that the presence of this influenza specific KLRG1hiCD57hi T cell population was a predictor of a poor antibody response to vaccination to seasonal H1N1 influenza (9). We also examined the state of immunity to A/2009 pandemic influenza in the Toronto population at 1 year post-pandemic(10).

Another aspect of our work has been to investigate the role of TNFR signaling in lymphocyte survival. We showed that the signaling adaptor TRAF1 was critical for the survival of activated T cells (11, 12). However, others had shown TRAF1 is a negative regulator of immunity. Recently we resolved this paradox by showing that TRAF1 is a positive regulator of classical NF-κB signaling downstream of 4-1BB In T cells, but negatively regulates the alternative NF-κB and cytokine productions in anti-CD3 activated T cells (13). Current projects in our lab are investigating the role of TRAF1 in several human diseases, including cancer, autoimmunity and HIV.

Our research is funded by the Canadian Institutes for Health Research.